End-stage renal disease (ESRD) is a major public health problem in the US and is increasing in incidence and prevalence, primarily due to an aging population with a higher incidence of diabetes and hypertension who are reaching ESRD. A major determinant of the quality of life in the elderly is the level of cognitive function. In the current proposal we plan to assess cognitive function in dialysis patients and to evaluate risk factors for cognitive impairment. Our primary hypothesis is that there is a high prevalence of cognitive impairment in dialysis patients, and that total plasma homocysteine (tHcy), oxidative stress and inflammation are associated with cognitive impairment via large and small vessel cerebrovascular disease. In the R21 phase of the grant we plan to assess the feasibility of recruiting 40 patients from the Boston Dialysis Clinic Inc. (DCI) unit and performing detailed cognitive testing and neurological exams, and assaying for tHcy, measures of oxidative stress and inflammatory markers. If the milestones are met for the R21 phase, we plan to proceed to the R33 phase and assemble a cohort of 250 dialysis patients from an additional 4 outpatient DCI units. The primary aims of the R33 will be to assess the range of cognitive function, and compare it with age, gender and education matched norms in the general population; to evaluate whether there is an association between tHcy, oxidant stress and inflammatory markers with cognitive function; and to evaluate risk factors for change in cognitive function over a two year follow-up. The principal investigator has assembled a multidisciplinary research team consisting of world-renowned experts in each of their respective fields. The most up-to-date biological assays will be used to evaluate the primary risk factors of interest. Validated neurocognitive assessment instruments will be used to assess the primary outcome of cognitive function. Plans have been developed for evaluation of generalizability, and statistical analyses suggest adequate power to evaluate each of the primary aims. Cognitive impairment adversely affects the quality of life of the aging population. There are limited data on cognitive function in dialysis patients, and cognitive impairment is likely to become more of a problem as the dialysis population ages. Evaluating the prevalence of, as well as potential risk factors for, cognitive impairment may lead to intervention trials to reduce the burden of cognitive impairment in this patient population.